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United States Patent O?lce
3,036,116
Patented May 22, 1962
1
2
groups being present can be split, if necessary, by treat
3,036,116
Hans Muxfeldt, Braunschweig, Germany, assignor to
~ ' ‘ ‘1H
ment with acids to free 'hydroxyl groups.
CENE A€IDS AND PROCESS
'
The compounds that come into consideration as start
ing substances ‘and correspond to the general formula
Farbwerke Hoechst Aktiengesellschaft vorrnals Meister
Lucius & Briining, Frankfurt am Main, Germany, a 5
1': on,
corporation of Germany
.
No Drawing. Filed Nov. 19, 1959, Ser. No. 854,023
Claims priority, application Germany Nov. 22, 1958
8 Claims.
(Cl. 260-473)
’
Antibiotics of the general formula
O Alk
O Alk
can be obtained by condensation of meta~methoxy~aceto
phenone with a succinic acid ester and subsequent cat
15 alytic hydrogenation of the cis- or trans(meta-methoxy
phenyl) -p-carbalkoxy-va1eric acid, chlorination of the
in which X represents hydrogen or chlorine, Y represents
hydrogen or—in case X stands for hydrogen-also the
same and treatment of the reaction mixture with poly
phosphoric acid at an elevated temperature, separation of
the cis- or trans-8-methoxy-5-chloro-4-methyl-3-carbalk
20 oxy-tetralone, bromination of the same and elimination
of hydrogen bromide from the compounds obtained. ' For
the reduction to the corresponding alcohols there are suit~
hydroxy group, have gained great importance in phar
able acid halides as well'as acid esters. As acid halide
macy. Upto the present day the‘ compounds are pre
there is preferably used the acid bromide and particularly
pared by biological processes. The only synthesis of such 25 the acid chloride, whereas as esters there come above all
tetracyclic compounds or such degradation products con
into consideration compounds that are derived from low
taining the tetracyclic ring system has not yet been de
molecular, aliphatic alcohols containing 1 to 4'carbon
scribed.
atoms such as methanol or ethanol.
L Now it has been found that there are obtained in a good
The reduction is
carried out with the use of complex metal hydrides, par
yield compounds of the general formula
ticularly lithium ‘aluminium hydride. The transformation
of the acid derivatives into the alcohols is carried out
in inert solvents. Preferably there are used others; cyclic
ethers being also suitable. There may, for example, be
mentioned: diethyl ether, dioxane and tetrahydrofurane.
35 Hydrocarbons may also be used as solvents.
The re
action temperature is advantageously chosen between
0 Alk
—20° C. and _+50° C.
o Alk \0
The alcohols obtained are then transformed in a man
_ ner known per se into the corresponding halides or tosyl
in which X represents hydrogen or chlorine, R1 and R2
stand for a carboxy or carbalkoxy group (R1' may also 40 ates. For the preparation of hydrohalic acid esters there
stand for hydrogen) and alk represents a lower molecu
come into consideration the customarily used agents such
lar alkyl radical, particularly methyl, by transforming by
as phosphorus tri- or pentrabromide or also thionyl chlo
reduction compounds of the general formula
ride. It is of vadvantage to add a small amount of pyridine
to the reaction mixture. In this reaction stage the re
CH3
4.5 action temperature should not exceed 50° C. The reac
CO-A
tion itself is carried out in the presence of diluents. As
such there are suitable ethers, hydrocarbons and above
all low molecular aliphatic chlorinated hydrocarbons.
The transformation into the para-toluene-sulfonic acid
Olllk \O Alk
50 ester is advantageously carried out with para-tosyl chlo
ride in absolute pyridine.
in which X has the meaning given above and A repre
In order to come from the two-membered ring system
7 of the naphthalene molecule to the three-membered ring
sents a halogen atom, especially chlorine or bromine, or
an O-alkyl group, into alcohols of the general formula
II(
system of the anthracene it is necessary to extend the
methylene group being present in the form of the hydro
CH3
A
halic acid ester or para-toluene-sulfonic acid ester by con
densation with suitable compounds. As suitable com
pounds there come into consideration carbalkoxy-succinic
acid dialkyl esters or carbalkoxy-methyl-malonic acid di
alkyl esters in the form of their alkali metal compounds.
These alkali metal compounds can be prepared by means
of the free alkali metals, preferably by means of alkali
metal hydrides or amides. The reaction is carried out in
FCl-IzOH
Y
OAlk
OAlk
by converting these into the corresponding hydrohalic
acid esters or para-toluene~sulfonic acid esters, by con
densing the compounds obtained with sodium carbethoxy
succinic acid dialkyl esters or with carbethoxy-methyl
malonic acid dialkyl esters, by cyclisizing the compounds
obtained by treatment with polyphosphoric acid and, if
necessary, by hydrolyzing the esteri?ed carboxyl groups
that may still be present to free carboxyl groups and, if
the presence of solvents. There are preferably used inert
65
solvents, above all ether such as diethyl ether, dioxane,
tetrahydrofurane and aromatic hydrocarbons such as
benzene and the like. However, there may also be used
other solvents such as alcohols. In this case, however,
it has to be considered that in the presence of alcohols the
solvolytic reaction takes place concurrently whereby the
desired, by transforming the dicarboxylic acids formed 70 yield
deteriorates.
by decarboxylation into monocarboxylic acids. Alkoxy
It has been found that the condensation products ob
3,036,116
,6
V
4
,
Example
tained are hydrolized relatively di?icultly if in the suc-7
cinic acid derivative or malonic- acid derivative used for
condensation all three carboxyl groups are esteri?ed with
(a) To a'vsolution of 104 grams of chloro-terranaphé
thoic acid dimethyl ether methyl ester. in one liter of
absolute ether there are added dropwise, while stirring
‘and cooling with ice, 275 cc. of a 1.5 N lithium alu
the same alcohol. Theproblem of the partial hydrolysis
can be solved, however, in an elegant and simple manner
by using for the condensation ditertiary butyl-mono-ethyl
minum hydride solution. When all of the solution has
been added, the reaction mixture is stirred for another
, derivatives. In ‘the- case of the partial hydrolysis merely ' 'hour,.the excess of the lithium aluminum hydride is can
esters of the succinic acid derivatives or of malonic acid
_ the ethyl ester group is split up to the free carboxyl group’
tiously destroyed by means of methanol and the reac
whereas the two tertiary butyl ester groups remain un 10 tion mixture is extracted by means ofZ N-hydrochloric
7 acid. The ether solution is diluted with 200 cc. of chlor0~
' According to the invention the cyclization of the con
form. and, after washing with water, and drying over
changed.
,
..
.
densation product to the vanthracene-one derivative is
sodium sulfate, the solvents‘ are completely distilled off.
,The crystalline residue is taken up in 200 cc.» of chloro
carried out with polyphosphoric acid under mild condi
tion's. When using tertiary butyl esters there is no evolu- 7
tion of isobutylene worth mentioning. Consequently, the ‘
cyclization product is obtained in a high yield.
7
- By means of the alkaline'agents customarily used for‘
hydrolysis the anthracene-one derivative obtained can be
form ‘and 1 liter of petroleum ether (boiling point 40
60° C.) is slowly added to the solution. The reaction
taneous splitting of the two alkoxyl groups into hydroxyl
groups. However, the ditertiary butyl esters can be by
drolyzed pyrolytically withia trace of an acid in an inert
dimethyl ether melting at 120° C.
mixture is allowed to stand for several hours and the
reduction product that has crystallized. out is then ?l
tered off withsuction. The precipitate is washed with
partially or completelyehydrolyzed and decarboxylated. 20 a little ether. There are thus obtained 74 grams (=79%
acid hydrolysis is generally only possible‘ with simul
of the theoretical yield) of the pure chloroterranaphthol
a
.
(b1) 20 grams of chloro-terranaphthol-dimethyl ether
are dissolved in 500 cc. of absolute chloroform and 0.2
solvent, for example benzene, with preservation of the 25 cc. of pyridine and 2.9 cc. of phosphorus tribromide are
alkoxygroups. The ditertiary butyl esters are already
added thereto. The mixture is boiled for 2 hours under
split quantitatively, while. heating for ?ve minutes with
re?ux. After cooling the reaction mixture is washed
dilute sodium hydroxide. solution, to the corresponding
'with water, sodium bicarbonate solution and again with,
dicarboxylic acid. The partial hydrolysis to the mono
water. The solution is then dried over sodium sulfate
‘carboxylic acid dicarbalkoxy derivative and the decal‘ 30 and the solvent is distilled o? under reduced pressure.
boxylation are carried out in known manner according
The crystalline residue represents the chloro-terranaph
to the customary methods of working.
a
thyl bromide dimethyl ether. The compound can directly‘
“ The alkoxy groups being present in the molecule can
already be completely dealkylated at room temperature
be used for further condensation.
within a short time by concentrated mineral acids so that
are dissolved in 300 cc. of absolute pyridine. 65 grams
(b2) 85 ‘grams of chloro-terranaphthol-dimethyl other
it is possible in this way to obtain the corresponding
of paraatosyl chloride are slowly added to the mass while
stirring vigorously and cooling, so that the temperature
does not exceed +5” C. The reaction mixture is then
dihydroxy compounds in a simple manner. The follow
ing scheme of formulae serves for elucidation of the
reaction sequencerdescribed in the example.
or
on,
or
on.
0000113
I
cont
or
A onion
A 0mm
-—-——)
-—--->
(a)
(hi)
v
7
00H.
oornv can;
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can,
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or
our
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1
a
ooomonr)
V
-
5
‘
01
0000mm),
V
ooh,
om
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con.
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on: /oooo(orn)a ’
‘7
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(d5)
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con.
C\
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i 0000mm).
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rn-oooolni
0
cont
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00m
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(49/
it!
'
7.
'
G1
00011
‘
00011‘
,
CH3
|
vids)‘
—---—>
\
QQHI
OCH;
0
' OCH:
005g 0
The products obtained by the process of -~ the present 70 allowedtostand for 12 hours in a refrigerator. It is
invention are valuable intermediate products forsynthesis
of pharmaceuticallyivaluable compounds such as those of
i l the tetracycline group.
' The following example ' serves’ to illustrate the inven
tion but it is not intended'to
it thereto:
—
diluted with 2 liters of chloroform, the pyridine is ex
tracted with ice cold dilute hydrochloric acid and the
chloroform solution is washed with sodium bicarbonate
and water. After'drying over~sodium sulfate the sol-'
vent is distilled off at 40°
under reduced pressure.
5
3,036,116
The crystalline residue represents the tosylate of the
ohloro-terranaphthol dimethyl ether than can directly be
01
I
used for condensation with the sodium carbethoxy
CE:
CO 0 C (CH3)3
OHr-O-CO O 0 (CH3);
methyl-malonic acid ester without further puri?cation.
(01) 100 grams of chloro-terranaphthol-dimethyl ether
011200 0 CrHs
are transformed with phosphorus tribromide into the
bromide as described under (b1). 120 grams of carb
/
|
OCH3 OCH:
ethoxy-succinic ‘acid diethyl ester are slowly added drop
Wise to a suspension of 20 grams of sodium hydride in
200 cc. of benzene, the mixture is stirred at room tem
10 amounts to 148 grams (84% of the theoretical yield).
perature until the evolution of hydrogen has ceased (about
3 hours). The solution is decanted from the sodium
hydride, combined with a solution of the terranaphthyl
bromide dimethyl ether in 500 cc. of absolute benzene
and boiled for 2 hours under re?ux. Aftere cooling, the 15
A sample of the compound recrystallized repeatedly from
methanol melts at 94—95° C. However, the raw prod
uct can be subjected without further puri?cation to the
cyclization reaction and partial hydrolysis hereinafter de
scribed.
(dl) 132 grams of the dimethyl ether of the ot-(chloro
reaction mixture is diluted with 500 cc. of ether, washed
terranaphthyl)-a-carbethoxy-succinic acid diethyl ester
with 1 N-hydrochloric acid and water, dried and the sol
are heated to boiling for 35 minutes under re?ux with
vent is completely distilled o?'. The yellow brown resi
1.5 liters of an ethanolic potassium hydroxide solution
due is mixed with 100 cc. of methanol and, when the 20 of 5% strength. The mixture is then poured into 2
crystallization has set in, allowed to stand for several
liters of Water, extracted by means of ether, the aqueous
hours in the deep-freezing refrigerator. The mother liq
phase is acidi?ed with dilute hydrochloric acid and ex
tracted with chloroform. The chloroform extract is
uor is ?ltered o? with suction and the ?lter residue is
washed with water, dried and the solvent is completely
washed well with methanol. By concentrating the ?ltrate
a further fraction crystallizes out in the deep-freezing re 25 distilled oft". The residue is mixed with 150 cc. of gla
cial acetic acid and the solution is stirred for 25 min
frigerator. There are obtained altogether 135 grams
utes at 70° C. with 500 cc. of p'olyphosphoric acid. The
(75% of the theoretical yield) of the dimethyl ether of
mixture is then poured on ice water. The reaction prod
i the a-(chloroterranaphthyl) -u-carbethoxy-succinic acid di
uct is extracted with ether. The extract is freed by ?l
ethyl ester melting at 8l~83° C. After repeated recrys
tallization from methanol the compound has a constant 30 tration from black ?occulant impurities, washed with
.sodium carbonate solution and water, dried and ?nally
melting point of 83—84° C.
evaporated. ‘There remain 66 grams of a brown oil that
(c2)(a) 290 grams of malonic acid ditertiary butyl
is mixed with 100 cc. of ether. When the crystallization
ester are added to a solution of 33.5 grams of sodium
has set in, the mixture is allowed to stand for several
in 750 cc. of absolute ethanol. To this mixture there 35 hours in the deep-freezing refrigerator. The crystals that
are added dropwise 250 grams of bromoacetic acid ethyl
have precipitated are separated from the solution by
ester. The reaction mixture is then heated for 15 min
?ltering with suction and the ?lter residue is washed
utes on the boiling water bath, diluted with 3 liters of
well with ether. There are obtained 10.2 grams ('=8.5%
water, the ester is extracted by means of ether and the
of the theoretical yield) of the 1.2.3.4-tetrahydro-3.3
.dicarbethoxy - 9 - methyl - 5- chloro - 8.10 - dimethoxy
ether solution is distilled after washing with water and
anthracene-l-one. The compound melts at 120—l23° C.
drying’over sodium sulfate. There remains an oil that
A sample recrystallized repeatedly from methanol melts
is distilled under reduced pressure. There are obtained
at l24.5—l26.5° C.
130 grams of a fraction boiling between 161 and 163°
(d2) From the ?ltrate of the product obtained accord
C. (14 mm.) that represents the carbethoxy-methyl-ma
lonic acid ditertiary butyl ester.
45 ing to (dl) the solvent is completely distilled off. The
residue is taken up in benzene and the solution obtained
(02) (,3) 85 grams of the dimethyl ether of the chloro
is ?ltered through a column of acid silica gel. Benzene
terranaphthol are transformed into the bromide or to
is used for the additional washing. The ?ltrate is com
sylate in the manner described under (b1) or (b2). From
pletely evaporated and the oily residue (45 grams) is
the bromide or tosylate obtained there is prepared a solu
50 boiled for 1 hour under re?ux with 100 cc. of methanol
tion in 400 cc. of absolute benzene.
and 100 cc. of a sodium hydroxide solution of 10%
In addition, there is prepared a solution of sodium
strength, in which 2 grams of sodium 'dithionite are dis
car-bethoxy-methyl-malonic acid ditertiary butyl ester in
solved. The yellow brown solution is diluted with 500
tetrahydrofurane by slowly adding dropwise 92 grams of
the ester into a suspension of 20 grams of sodium hy 55 cc. of water and acidi?ed. The‘ reaction mixture is
allowed to stand for several hours, the semi-solid pre
dride in 400 cc. of absolute tetrahydrofurane, stirring
cipitate is ?ltered off with suction and recrystallized
the mixture for 3 hours at room temperature and de
from 50 cc. of glacial acetic acid. The crystallisate that
canting the solution from the sodium'hydride in ex
has separated is ?ltered o?'ywith suction after sometime
cess. The solution thus obtained is combined with the
solution of the bromide or tosylate, the main quantity 60 and the ?lter residue is washed ‘well with chloroform
and ether. There are thus obtained 11.2 gramsof va
of the tetrahydrofurane is distilled o? ‘with exclusion of
humidity and the remaining benzene solution is boiled
for two hours under re?ux. After cooling the solu
ton is washed with l/ioo N-hydrochloric acid, dried and
freed from the solvent. The hot oily residue is taken up
in 300 cc. of methanol.
dicarboxylic acid of the formula
65
01
I
on.»
/
The crystallization of the con
densation product sets in after a short time. The whole
is allowed to stand ‘for several hours, the crystallisate
that has separated is ?ltered off ‘with suction and washed
with methanol. By concentrating the mother liquor
there is obtained a second fraction, the mother liquor
00011
OOOH‘
§
OCH3 OOH3 O
that can be worked up without further puri?cation.
of which yields a third fraction upon standing in the
The solvent is completely distilled off from the mother
deep-freezing refrigerator. The total yield of the con
liquor, the residue is taken up in 50 cc. of phthalic acid
densation product of the formula
75 diethyl ester, and the solution isheated to 170° C. un
3,036,116
.7
"4
tracted exhaustively with a sodium carbonate solution of
5% strength, the sodium carbonate extract is acidi?ed,
the acidi?ed extract is extracted with chloroform and
the chloroform solution is adsorbed at acid silica gel.
On washing with chloroform a light yellow zone passes
quickly through the column, the eluate of which is re
' jected.
8
‘(d5)’ 1403mm? of the ester of the-formula
til no more carbon dioxide evolves. After cooling the
reaction mixture is diluted with 300 cc. of ether; ex
~
'
oi
"
"on;
l '
'
'
;
, ,
"~
-
-
-
.
'/oooo(on3>3
c?iéceoooctonag,"
‘
'
"
~
061-13 (i‘bOHg .
From the dark?brown zone adhering to the up
per part of the column there separates slowly a deep 10 are dissolved in 1500 cc. of boiling methanol. To the so
lution there are added within _5 minutes 350 ccl of an
yellow zonejthat‘ is eluated, after cutting up the col
aqueous potassium hydroxide solution of 5% strength.
umn, by'rm‘eans of a mixture of chloroform and ace
tone in a proportion of‘ 10:1. ‘The eluate is ‘concen
trated, taken up in- 10 cc. of ‘acetone and 150 cc; of
v‘benzene, and the acetone is distilled off 'azeotropic'ally. .
The mixture is boiled for about 20 minutes until a sam
ple of the solution does no, longer become turbid when
diluted {with water. The brown solution of the partially
hydrolyzed ester is shaken with a little animal charcoal,
?ltered and acidi?ed. The monocar-boxylic acid of the
After standing for several hours the 1.2.3.4-tetrahydro
3.3 - dicarbethoxy - 9 {methyl -_ S'- chloro - 8.10 - di- '
methoxy-anthracene-l-one that has crystallized out is
separated from the mother liquor by ?ltering with suc
tion. The ?lter residue is'washed with ether and dried.
The yield of monocarboxylic acid amounts to 3.6 grams.
formula
Cl
CH3
1
_
' (d3) 10.2 grams of 1.2.3.4-tetrahydro-3.3-carhethoxy-9
methMAS-chIOro-S.IO-dimethoxy-anthracenedeone
V
COOG(OH:.)a
CH2——G—COOC(CH3)3
C'HaCOOH
(ob
tained in the manner as described under ((11)) are
OCHs OCHs
boiled’ for one hour under reflux With'a mixture of 75
cc. of methanol and 75 cc. of a sodium hydroxide solu»
tion of 10% strength containing 2 grams of sodium
that separates is extracted with chloroform, the chloro
with 500cc.‘ of hot‘water and the boiling solution is
acidi?ed. After cooling the reaction product that has
form extract is dried and the solvent is distilled off. The
residue is‘taken up in 250 cc. of glacial acetic acid and
30 the solution is diluted with‘ 1500 cc. of polyphosphoric
crystallizedrout is ?ltered off with suction,v the ?lter resi
due is washed well with water and dried. The yield of
The solution turning deep red is poured, While stirring
dithionite in the dissolved state,’ the solution is diluted 7
acid.
vigorously, into vmuch water and the reaction product
dicar-boxylic acid (formula-see under (d2)) amounts
is extracted with ether. The ether extract is freed by
to 8.40’ grams (94% of thevtheoretical yield). vWhen
heated the compound melts between 165 ‘and 170° C.
with evolution of carbon dioxide.
?ltration from black ?occulent decomposition products
and exhaustively extracted with sodium carbonate solu_
tion. The ether extract is Washed well vw'th viZter, 300
'
11,4) The 8.40Qgrarns or 11.2 grams of dicarboxylic acid
of the
formula
'
'
Cl
"
i
.
p
.
CH3_
V
V.
.
'
‘
»
cc. of benzene are added thereto and the mixture is dried
over sodium sulfate. After elimination of the solvent
40 there remain 104 grams of a yellow oil that crystallizes
upon trituration with 200 cc. of ether. There is thus
obtained a ?rst fraction of the compound of the formu
la
.
e
The mixture is then heated for 2 hours at 60° C.
coon
/
coon
01
V
OCHaYCH; O‘ 7'
\
CH3
'45
t
obtained by the hydrolysis as described under (rig) and
A
COOC(UHa)a
(d3) are suspended in .75 cc. of phthalic acid diethyl
ester. The mixture is heated in an oil bath to 170° C.
After the evolution of carbon dioxide has ceased the re 50
action mixture is diluted with 200‘ cc. of ether and al
in a quantity of 64 grams. By concentrating the mother
lowed to stand for several hours. The crystal magma that
liquor a second fraction of the compound is obtained
has separated is ?ltered ‘oif with suction’ and carefully
in a quantity of 16 grams. The remaining mother liquor
washediwith ether. The ?ltrate isexhaustively extracted
is
freed from the'ether, the’ residue is dissolved in benzene
55
with a sodium carbonate‘solution of 5% strength, the
and the solution is ?ltered through a silica gel column.
vacidi?ed sodium- carbonatepsolu'tion is extracted with
The'?ltrate is evaporated. By trituration of the residue
chloroform, the chloroform extract is concentrated to
06H; <i)<3£u\0
50 cc. and allowed to’ stand for several hours.
The
precipitate that has separated is ?ltered off with suction
and’ washed well with'ea little chloroform. The mother 60
liquor is adsorbed on acid silica gel, After a weakly
yellowish zone has been eluated when washing with chlo
with ether a third fraction amounting to 8 grams is ob
tained so that the total yield of the compound of the
formula‘
7
~
. (El
the column is cut outrand eluated with a mixture of
chloroform and acetone in a proportion of l0:1. The 65
1
'
'
/0 0 o (one).
COOCgCHQB
reform, the deep yellow zone slowly passing through
.Veluate is evaporated to dryness, the residue is’ takenup
‘
l
\
00113 00m 0‘
in a mixture of 10 cc. of'acetone and 15 cc. of benzene
and the acetone is distilled off azeotropically. The so
amounts to 88 grains (=70% of the theoretical yield).
lution is allowed to stand for several hours and the third
fraction of 1.2.3.4-tetrahydro-3-carboxy-9~methyl-5-chlo 70 The .raw producti'thus obtained that can be’ hydrolyzed
without further puri?cation to the free dicarboxylic acid,
ro-8.lO-dimethoxyanthracene-ljone that has separated is
melts between 126° C; and 130° C., whereas asample
?ltered oif withsuction. ‘The ?lter residue is washed ‘with’
recrystallized from methanol melts at 131—132‘? C.
. ether and dried. Therefare, obtained altogether 13.2
(d6)‘ 84 grainsof the tertiary butyl ester obtained ac
‘ .igrams (=88% of the theoretical‘ yield) of the said com
75 cording tottis) are dissolved in 1 liter of methanol and
' ‘pound melting at 218-220" .C.
' '
'
.
3,036,116
10
the solution is heated to boiling. To the boiling solu
tion there are added dropwise, within 10 minutes, 500 cc.
of sodium hydroxide solution of 20% strength in which
5 grams of sodium dithionite had previously been dis
solved. The mixture is boiled for a further 5 minutes
under re?ux, diluted with 3 liters of boiling ‘water and
acidi?ed with concentrated hydrochloric acid. After
cooling the dicarboxylic acid of the formula
4. The compound of the formula
C1
CODE
5
;
<COOH
00113 ([30:53 \0
(ill CH3
OOOH
10
5. The compound of the formula
(11
CODE
OCH3
CH3
|
\
OGHQ O
OH,
15
—CO0H
I
that has crystallized out is ?ltered off with suction, the
\
?lter residue is washed with water and dried under re
duced pressure. There are obtained 62 grams (=96%
of the theoretical yield) of dicarboxylic acid.
(d7) 200 milligrams of carboxy-S-chloro-S.9-dimeth
OCHa 60113 \O
20
6. The method of making a compound of the formula
01
oxy - 10 - methyl - 1.2.3.4 - tetrahydro - anthracene - 1
one are dissolved in 5 cc. of hot glacial acetic acid. 20
cc. of concentrated hydrochloric acid are added to the
CH3
I
/R1
\R2
solution and the mixture is allowed to stand for 3 hours
25
at room temperature. The solution that is at ?rst red
and later on turns yellow, from which the demethylation
product has partly separated, is diluted with water and
the mixture is extracted with chloroform.
01130
When con
OCH3\O
wherein R1 and R2 are selected from the group consisting
centrating the chloroform extract the 3-carboxy-S-chlo 30 of carbethoxy and carbo-t-butoxy which comprises con—
ro-8 .9-dihydroxy- lO-methyl- l .2. 3 .4-tetrahydro-anthracene
tacting a ?rst compound of the formula
l-one separates in the form of orange crystals. The yield
amounts to 162 milligrams (=88% of the theoretical
('31 CH3
yield). After repeated recrystallization from benzene the
compound melts at 196-197“ C.
(JO-A
35
I claim:
1. A compound of the formula
01
I
CH;
01130
R,
(I) CH3
40 where A is a member selected from the group consisting
R2
|
CHaO
OCHs
\
0
of chlorine, bromine, and alkoxy the alkyl portion of
which has 1 to 4 carbon atoms, with lithium aluminum hy
dride, whereby said ?rst compound is reduced to form an
alcohol; then contacting said alcohol with a member of
wherein R1 is a member selected from the group con 45 the group consisting of phosphorus tribromide, phos
sisting of hydrogen, carboxy, and carbalkoxy the alkyl
portion of which has 1 to 4 carbon atoms, and R2 is a
member selected from the group consisting of carboxy
and carbalkoxy the alkyl portion of which has 1 to 4
carbon atoms.
'
2. A compound of the vformula
o1
CH5
I
000211];
I
0 CH3 OCH;
OOOalk
\
0
wherein alk stands for alkyl having up to 4 carbon atoms.
3. A compound of the formula
C1
CH3
C 0 0C (CH3):
C O O C (011a):
\
com 0011, 0
phorus pentabromide, thionyl chloride, and paratoluene
sulfonic acid chloride, whereby a second compound, cor~
responding with halides and tosylates of said alcohol, is
formed; then contacting said second compound with a
member of the group consisting of sodium carbethoxy
succinic acid diethyl ester and sodium carbethoxy methyl
malonic acid di-t-butyl ester, whereby a third compound,
which is -a condensate of the reactants, is formed; and
then contacting said third compound with polyphosphoric
55 vacid, whereby said third compound is cyclized to form the
product.
7. A method as in claim 6 wherein said product is
contacted with a dilute solution of an alkali metal hy
droxide, whereby said groups R1 and R2 are hydrolyzed‘
to carboxy groups to form a dicarboxylic acid.
8. A method as in claim 7 wherein said dicarboxylic
acid is heated at a temperature above 170° 0., whereby
decarboxylation occurs and a monocarboxylic acid is.
formed.
References Cited in the ?le of this patent
Muxfeldt et tal.: Chem. Abst., 53, 16088, Sept. 10, 1959
(citing Abhandl, Brauuschweig. wiss. Gm, 10, 1 to 8
(19.58)):